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The capacity of imatinib mesylate to reverse established pulmonary arterial hypertension (PAH) has been attributed to a reduction in pulmonary arterial muscularization via inhibition of platelet-derived growth factor receptor-β on vascular smooth muscle cells. However, there is also a significant immunomodulatory component to the action of imatinib that may account for its efficacy in PAH. We found that monocrotaline-induced pulmonary hypertension was associated with a significant decrease in pulmonary natural killer (NK) cells and T lymphocytes and the accumulation of macrophages in the lungs of F344 rats. The prevention of pulmonary hypertension by imatinib blocked these changes in pulmonary leukocyte content and induced elevations in pulmonary interferon-γ, tumor necrosis factor α, and IL-10, corresponding to the enhanced activity of splenic NK cells ex vivo . Treatment with anti–asialo GM1 antiserum (ASGM1), which ablated circulating NK cells and depleted T cells, eliminated the therapeutic benefit of imatinib. ASGM1-treated animals also exhibited significant pulmonary arteriolar muscularization in response to monocrotaline challenge compared with immunocompetent controls despite daily imatinib administration to both groups. In the athymic rat, imatinib decreased right ventricular hypertrophy and pulmonary arteriolar muscularization in monocrotaline-challenged animals versus saline-treated controls but did not prevent pulmonary macrophage accumulation or the development of pulmonary hypertension. These data demonstrate that the immunomodulatory effects of imatinib are critical to its therapeutic action in experimental PAH.

In a distributed object system, metadata provides a concise description of the object that can be distributed broadly. The actual data that represents the complete object is often very large and hence can be time consuming to transfer. Metadata is an enabler for the wide area distribution of objects along potentially unreliable and low speed channels. The metadata could go first and the actual data would follow only if needed. Data provenance is the chronology of an object, i.e. a record of all of the transformations and actions that modified the state of the object from the time of creation to the present time. End-to-end data provenance is the ability to account not only for the data provenance of a single object, but also to account recursively for the data provenance of all other objects that affected the state of the object. Loose coupling of metadata and actual data is well understood for static, unchanging data. Systems across many industries allow remote browsing of metadata representing huge datasets and the selective movement of actual data. For example every content delivery network (CDN) employs loose coupling of metadata and actual data to deliver movies, videos, books and other types of static data. The problem yet to be solved is the one in which the actual data is changing over time. This is an important use case in shared earth problems. As modeling of the subsurface increases and is used by larger, more geographically disperse teams, there is a need for a system that supports the special requirements of shared earth modeling. These requirements include the need to support parallel changes to objects, support for slow and unreliable networks, and the ability to work disconnected from a central repository. Such a system is presented in this paper. This paper is a follow on to SPE 174803, End-to-End Data Provenance.

SUMMARY A comprehensive study has been made on the serum proteins in patients with Down's syndrome. The methods used were electrophoresis (serum proteins and glycoproteins), colorimetry (s-lipoproteins), radial diffusion (group-specific proteins, α1-antitrypsin, s1-A-globulin, transferrin, α1-acid glycoproteins, haptoglobin, ceruloplasmin, s1-E-globulin, s2-glycoprotein, α2-HS-glycoprotein, pre-albumin, α2-macroglobulin, haemope in, IgA, IgD, IgG and IgM), and radial double diffusion and immunoelectrophoresis (29 specific proteins). Significant reductions were found in the levels of total protein, albumin, α2-globulins, s-globulins (quantitative) and in the α1- and s-glycoproteins (percentage). Significant elevations were found in the α1-acid glycoprotein (quantitative) and in the IgA and IgD fractions. The literature on serum protein in Down's syndrome is reviewed and the findings in the present investigation are discussed in relation to the previously reported divergent findings on this subject. RESUME Proteines seriques dans le mongolisme Une etude systematique a ete conduite sur les proteines seriques chez les mongoliens. Les methodes utilisees ont ete l'electrophorese (proteines seriques et glycoproteines), la colorimetrie (s1-lipoproteines), la diffusion radiale (groupe specifique de proteines, α1- anti-trypsine, s1-A-globuline, transferrine, α1-glycoproteines acides, haptoglobine, cerul plasmine, s1-E-globuline, s2-glycoproteine, α2-HS-glycoproteine, pre-albulmine, α2-macroglobuline, hemopexine, IgA, IgD, IgG et IgM), et la diffusion radiale double et l'immuno-electrophorese (29 proteines specifiques). Des reductions significatives ont ete trouvees dans les taux de proteines, albumine, α2-globulines s-globulines (quantitative) et dans le α1 - et le s-glycoproteines (pourcentage). Des augmentations significatives ont ete trouvees pour les α1-glycoproteine acide (quantitative) et dans les fractions IgA et IgD. La litterature sur les proteines seriques dans le mongolisme est revue et les donnees de la recherche presente sont discutees en relation avec les donnees divergentes anterieurement rapportees sur le sujet. ZUSAMMENFASSUNG Serumproteine beim Down Syndrom Eine umfassende Studie der Serumproteine bei Patienten mit Down Syndrom wurde durchgefuhrt. Folgende Testmethoden wurden angewandt: Elektrophorese (Serumproteine und Glucoproteine), Colorimetrie (s1 - Lipoproteine), Radialimmundiffusion (Gruppenspezifische Proteine, α1-antitrypsin, s1-A-globulin, Transferrin, saure α1-Glucoproteine, Haptoglobin, Coeruloplasmin, s1-E-Globulin, s2-Glucoprotein, α2-HS-Glucoprotein, Praalbumin, α2-Makroglobulin, Haemopexin, IgA, IgD, IgG, IgM), doppelte Radialdiffusionund Immunelektrophorese (29 spezifische Proteine). Eine signifikante Verminderung fand sich bei der Hohe des Gesamteiweises, des Albumins, der α2-Globuline, der s-Globuline (quantitativ und bei α1- und s-Glucoproteinen (prozentual). Eine signifikante Erhohung wurde bei den sauren α1-Glucoproteinen (quantitativ) und in den IgA- und IgD-Fraktionen gefunden. Die Literatur uber Serumproteinstudien beim Down Syndrom ist durchgesehen worden und die Befunde der vorliegenden Untersuchung wurden den abweichenden Befunden von fruheren Untersuchungen gegenubergestellt. RESUMEN Proteinas sericas en el sindrome de Down Se ha realizado un estudio de las proteinas sericas en pacientes con el sindrome de Down. Los metodos usados fueron: electroforesis (proteina sericas y glucoproteinas). colorimetria (s1-lipoproteinas), difusion radial (proteinas especificas de grupo α1-antitripsina, s1-A-globulina, transferrina, α1-acido glucoproteinas, haptoglobina, ceruloplasmina, s1-E-globulin, s2-glucoproteina, α2-HS-glucoproteina, pre-albumina, α2-macroglobulina, hemo-pexina, IgA, IgD, IgG y IgM) y doble difusion e inmunoelectroforesis (29 proteinas especificas). Se encontraron reducciones significativas en los niveles de proteina total, albumina α2 globulinas, s-globulinas (cuantitativa) y α1- y s-glucoproteinas (porcentual). Elevaciones significativas se hallaron en α1-acido glucoproteina (cuantitativa) y en las fracciones IgA y IgD. Se revisa la literatura sobre proteinas sericas en el sindrome de Down y se discuten los hallazgos de la investigacion presente en relacion con los hallazgos divergentes sobre este tema publicados anteriormente.

The serum levels of alpha2-macroglobulin (alpha2-MG) were determined by radial diffusion if fifty-four cases with tuberose sclerosis and compared with forty-seven institutionalised control subjects of similar age and sex distribution. Although higher levels of alpha2-MG were found in the females of both groups when compared with the males, this increase was not significant. The tuberose sclerosis subjects showed consistently elevated levels of alpha2-MG when compared to the control group for both the males and females separately and combined. With the two sexes combined this elevation was significant at p less than 0.001. The significance of this observation has been discussed both from the point of view of the possible mechanism involved and the use of this estimation in genetical counselling.

Seventeen mentally handicapped patients with SIB (head banger) group are compared with a non-SIB group of similar grade and their behavioural and psychiatric ratings described. The recognition of a specific syndrome in SIB group is demonstrated and shown to lead to serious psychiatric disturbances. The importance of psychiatric diagnosis and treatment intervention among such a group is described. Language: en

A small thirty-eight-year-old profoundly retarded woman is decribed who has a ring chromosome identified by banding techniques. Details are given of her behaviour, anthropometry, dermatoglyphics, karyotype and biochemistry with extensive investigations of her blood proteins and enzymes. Other described cases of ring 21 and 22 are reviewed. There is so much variability among the ring 22 chromosomes that it is not considered justifiable to speak of a ring 22 syndrome.

The quantitative levels of seven of the acute-phase reactant proteins were measured in the plasma of a sample of fifty-four adults all diagnosed as suffering from tuberose sclerosis and compared to that derived from a group of control subjects resident in a hospital for the mentally subnormal. Abnormal levels were found in one or more of the proteins in all but thirteen cases, with no fewer than twenty-six subject (forty-eight per cent) showing results outside the 2SD limits in three or more of the parameters investigated. Only in the alpha1-antitrypsin and fibrinogen were the means not significantly different from the control means but even in these two proteins ten and seven cases respectively individually exceeded the normal mean by more than 2SD. It is suggested that these observations can be explained as the normal response to the presence of neoplastic tissue, and the routine investigation of these and other biochemical components known to respond to the presence of neoplastic tissue may be of help in genetic counselling.

Dibucaine, fluoride and RO2-0683 inhibition studies were used to determine the serum cholinesterase (pseudocholinesterase) phenotypes at the E1 locus in a sample of 130 subject with Down's syndrome and fifty-three mentally retarded control subjects. No example of the Ef1 and Es1 allele was detected in either group, nor were any of the genotype E1a E1a detected. The gene frequency of E1a for the control group (0.0189) resembles closely that reported in the literature for normal European populations but in the Down's group was significantly lower (0.0038). The means and distribution of the dibucaine, fluoride and RO numbers in both groups were similar to those reported in normal subjects. The presence of the additional C5 cholinesterase type heterozygous for a variant cholinesterase on the E2 locus) was detected after starch gel electrophoresis, and the frequency was found to be raised in both groups. Several possible environmental factors (age, sex, maternal age, etc.) were investigated to account for this finding but with no success.

Data provenance is the chronology of an object, i.e., all the transformations and actions that modified the state of the object from the time of creation to the present. End-to-end data provenance is the ability to account not only for the data provenance of a single object, but also to account recursively for the data provenance of all other objects that affected the state of the object. The purpose of data provenance is to help ensure data integrity. Modeling has become an important aspect of shared earth problems. As the role and extent of modeling of the subsurface expands and its use is taken up by larger teams, determining the provenance of data becomes ever more important. The explosion of data and the appearance of increasingly diverse teams require the establishment of better data provenance to guard the integrity of the modeling results. Such a data provenance model is presented in this paper. The economic consequences of such an approach are significant: better integrity of modeling results leads to more confidence in those results, which reduces perceived risk and, in turn, can improve the economic performance of field development. The solution to the problem of end-to-end data provenance has six elements: The ability to uniquely identify objects of the shared earth problemAn object repository that supports federation and extensibilityThe ability to associate an immutable change history with each objectThe loose coupling of metadata and actual data of an objectClient-side caching of actual dataA comprehensive security model for the object. Each of these elements solves an important aspect of ensuring data integrity. Such an approach is increasingly important as model-based approaches become ubiquitous, and the available data become more voluminous, and the teams that handle the data and modeling results become larger and more diverse.

Using a chemical genetics screen, we have identified ent-15-oxokaurenoic acid (EKA) as a chemical that causes prolonged mitotic arrest at a stage resembling prometaphase. EKA inhibits the association of the mitotic motor protein centromeric protein E with kinetochores and inhibits chromosome movement. Unlike most antimitotic agents, EKA does not inhibit the polymerization or depolymerization of tubulin. To identify EKA-interacting proteins, we used a cell-permeable biotinylated form that retains biological activity to isolate binding proteins from living cells. Mass spectrometric analysis identified six EKA-binding proteins, including Ran-binding protein 2, a kinetochore protein whose depletion by small interfering RNA causes a similar mitotic arrest phenotype.

Checkpoints activated in response to DNA damage cause arrest in the G(1) and G(2) phases of the cell cycle. Inhibitors of the G(2) checkpoint may be used as tools to study this response and also to increase the effectiveness of DNA-damaging therapies against cancers lacking p53 function. Using a cell-based assay for G(2) checkpoint inhibitors, we have screened extracts from the NCI National Institutes of Health Natural Products Repository and have identified 13-hydroxy-15-oxozoapatlin (OZ) from the African tree Parinari curatellifolia. Flow cytometry with a mitosis-specific antibody showed that checkpoint inhibition by OZ was maximal at 10 microm, which released 20% of irradiated MCF-7 cells expressing defective p53 and 30% of irradiated HCT116p53(-/-) cells from G(2) arrest. OZ additively increased the response to the checkpoint inhibitors isogranulatimide and debromohymenialdisine, but it did not augment the effects of UCN-01 or caffeine. Unlike other checkpoint inhibitors, OZ did not inhibit ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), Chk1, Chk2, Plk1, or Ser/Thr protein phosphatases in vitro. Treatment with OZ also caused G(2)-arrested and cycling cells to arrest in mitosis in a state resembling prometaphase. In these cells, the chromosomes were condensed and scattered over disordered mitotic spindles. The results demonstrate that OZ is both a G(2) checkpoint inhibitor and an antimitotic agent.

Cells can respond to DNA damage by activating checkpoints that delay cell cycle progression and allow time for DNA repair. Chemical inhibitors of the G(2) phase DNA damage checkpoint may be used as tools to understand better how the checkpoint is regulated and may be used to sensitize cancer cells to DNA-damaging therapies. However, few inhibitors are known. We used a cell-based assay to screen natural extracts for G(2) checkpoint inhibitors and identified debromohymenialdisine (DBH) from a marine sponge. DBH is distinct structurally from previously known G(2) checkpoint inhibitors. It inhibited the G(2) checkpoint with an IC(50) of 8 micrometer and showed moderate cytotoxicity (IC(50) = 25 micrometer) toward MCF-7 cells. DBH inhibited the checkpoint kinases Chk1 (IC(50) = 3 micrometer) and Chk2 (IC(50) = 3.5 micrometer) but not ataxia-telangiectasia mutated (ATM), ATM-Rad3-related protein, or DNA-dependent protein kinase in vitro, indicating that it blocks two major branches of the checkpoint pathway downstream of ATM. It did not cause the activation or inhibition of different signal transduction proteins, as determined by mobility shift analysis in Western blots, suggesting that it inhibits a narrow range of protein kinases in vivo.

Adefective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome.

A phenotypic cell-based assay for inhibitors of the G (2) DNA damage checkpoint was used to screen plant extracts from the US National Cancer Institute Natural Products Repository. It revealed activity in a methanol extract from the common ragweed Ambrosia artemisiifolia. Assay-guided fractionation led to the identification of the sesquiterpene lactones psilostachyins A and C as novel checkpoint inhibitors. Elimination of their alpha,beta-unsaturated carbonyl group caused a loss of activity, suggesting that the compounds can bind covalently to target proteins through Michael addition. Psilostachyins A and C also blocked cells in mitosis and caused the formation of aberrant microtubule spindles. However, the compounds did not interfere with microtubule polymerization in vitro. The related sesquiterpene lactones psilostachyin B, paulitin and isopaulitin were also isolated from the same extract but showed no checkpoint inhibition. The identification of the target(s) of psilostachyins A and C may provide further insight into the signalling pathways involved in cell cycle arrest and mitotic progression.

Objective: This study evaluated various physical properties of two resin composites polymerized by either an argon laser or a conventional visible light. Materials and Methods: A hybrid composite, Herculite XRV (Kerr Corp., Orange, California), and a microfill composite, Durafill VS (Kulzer, Wehrheim, Germany), were used in this study. Three physical properties, diametral tensile strength, compressive strength, and flexural strength, were tested. Five specimens of each composite resin were made for each set of physical properties tested, for a total of 18 groups and 90 specimens. Specimens were fabricated according to the American National Standards Institute and American Dental Association Specification No. 27 for each property tested. The composite was polymerized with either an argon laser (power density of 1000 mW/cm2) for 10 or 20 seconds or a conventional visible light (power density of 354 mW/cm2) for 40 seconds. Specimens were stored in water in light-proof containers at 37°C for 7 days before testing with a Zwick (Atlanta, Georgia) universal testing machine. Results: The physical properties of Herculite XRV were not affected by the light source or exposure time. For Durafill VS, no significant differences were observed for the diametral tensile strength whether the argon laser or conventional light was used. However, the flexural strength of the microfill was significantly lower when polymerized with the argon laser a t 10 seconds compared with the two other curing methods (20-second laser cure, 40-second conventional cure). Also, the compressive strength of Durafill VS polymerized with the argon laser a t 10 seconds was significantly lower than when it was cured with the conventional light for 40 seconds. Conclusions: Hybrid and microfill resin composites cured with an argon laser for 20 seconds had physical properties comparable to composites polymerized with a conventional visible light unit for 40 seconds. Therefore, with adequate exposure time, the argon laser is a potential alternative to conventional visible light-curing.

Serum levels of the four main immunoglobulins, IgA, IgM, IgG and IgD were estimated in a sample of 54 subjects with tuberous sclerosis and the data compared with similar findings in a sample of 100 mentally retarded subjects chosen at random. Normal levels of IgA and IgD were found in the T.S. group, but elevated levels of IgM significant at P equals 0.001 was found in 49 of the 54 cases. A reduction in IgG levels (significant at P equals 0.001) was a much less constant feature being found in 29 of the 54 subjects. The significance of these results in the light of the observation that one of the principal causes of death in T.S. is from recurrent infection is discussed.

The serum levels of β2-glycoprotein 1 has been estimated on 381 healthy adult subjects of English origin. The frequency of the BgN gene was found to be 0.941 (S.E. 0.09) which is in close agreement with pooled data of Caucasian subjects of 0.937 (Koppe et al., 1970). The sample was shown to be bimodal, and composed of two non-overlapping normally distributed groups. One subject, presumable phenotypically BgD BgD was found in which no β2-glycoprotein 1 could be demonstrated. One significant difference between our population and that reported for other Caucasian populations was a significantly lower mean level of β2-glycoprotein 1 in subjects BgN BgN whereas no significant lowering of mean levels could be detected in the 43 subjects BgD BgD.

Haptoglobin phenotype frequencies for 887 unselected mentally retarded patients were within the range reported for normal European populations. Of these sera, 2% initially classified as anhaptoglobinemic by subjective appraisal of starch-gel electropherograms were subsequently shown to be hypohaptoglobinemic. This frequency of hypohaptoglobinemia is similar to that reported for normal populations. Sixteen of the hypohaptoglobinemic cases were reinvestigated, and all but one showed some evidence of hepatic dysfunction.

The levels of serum IgD-globulins in 59 cases of Down's syndrome and 59 mentally retarded subjects were estimated by radial diffusion. The mean for the Down's syndrome was 7.8 mg/100 ml and the controls 2.8 mg/100 ml, a difference which is significant at P = 0.01. Serum A/G and serum alkaline phosphatase were estimated and related to the IgD levels in an attempt to assess whether the elevation of the IgD was due to increased infection rates in Down's syndrome, and both were found to correlate with the IgD levels significantly. For A/G v IgD, r = −0.36, and for serum alkaline phosphatase v IgD, r = 0.38. No significant correlations could be detected in the control group. This evidence is taken to suggest that the increase in infections in Down's syndrome is responsible for the increase in IgD levels, but whether there is a modification of the normal response remains to be investigated.

The recent observation by Arndt-Hansen et al. (1974) of increased frequency of blood group A over group O in blood donors positive for the hepatitis associated antigen has been investigated in Down's syndrome, in order to establish if this could account for the increased frequency of the antigen in that syndrome. Seventy-one of 227 subjects with Down's syndrome (31.3%) were found to be positive for the antigen by haemagglutination, and comparison of these with the HAA-subjects failed to reveal any differences in the ABO blood groups.

A severely subnormal male with the syndrome of Coffin, Siris and Wegienka is described and compared with previously reported cases. The possible aetiology is discussed.

The observation elsewhere (Drew and Rundle, 1977) that increase frequencies of the C5 + variant of the serum cholinesterase in Down's syndrome may be due to a protective influence against adverse environmental factors has been investigated for such factors as age, sex, duration of institutionalisation, presence of the hepatitis -B antigen and maternal age. With the exception of the maternal age none of the factors tested appear to affect the circulating levels of cholinesterase. A maternal age effect in the Down's subjects was detected with lower levels of the enzyme being found in the subject positive for the C5 + variant born to mothers over thirty-five years when compared to the C5 + subjects born to mothers under thirty-five years. Further studies confirmed the presence of a relationship between maternal age, serum cholinesterase levels and haptoglobin phenotypes.

5 serum protein polymorphic systems (haptoglobin, alkaline phosphatase, group-specific (Gc) proteins, beta2-glycoprotein 1 and leucine aminopeptidase) and 6 red-cell polymorphisms (adenosine deaminase, adenylate kinase, phosphoglucomutase, glutamic-pyruvic transaminase, phosphogluconate dehydrogenase and acid phosphatase) have been investigated in 54 subjects with tuberous sclerosis. The frequencies of all systems were compared with those of a control sample drawn from a similar mentally retarded population and abnormal distributions were detected in the haptoglobin and Gc system. Quantitative estimation of the serum levels of the Gc protein failed to detect any inter-group differences. Data on the deviations from the Hardy-Weinberg equlibrium, Haldane's Log ratio test between groups, and gene frequencies of both test and control groups are given. It is suggested that selection by mortality is the possible causation for the abnormal distribution of the Gc phenotypes, but the haptoglobin phenotype distribution requires further investigation with care being taken in the selection of control subjects.

The red cell adenylate kinase (AK) phenotype was determined by starch gel electrophoresis in 96 adult Caucasian subjects with affective disorders (24 with bipolar illness and 72 with unipolar illness). The phenotype frequencies and the gene frequencies of the bipolar group closely resembled that of the control subjects (180 subjects drawn from the population of a large institution for the mentally retarded), the unipolar group however, showed a significant increase in the frequency of the AK2 allele. The significance of these results have been discussed in relation to the known genetic and biochemical findings in the affective disorders. It is suggested that the mechanism involved may be a reduction of the enzyme activity in the tissues of subjects with the AK 2:1 phenotype. This may present a selective disadvantage in the form of a decrease in control of energy metabolism in general, and control of adenine nucleotide levels in nervous tissue in particular.

The parental ages of 220 subjects with Down's syndrome and 106 control subjects is analysed with respect to the possible changes in heterozygous frequency for serum haptoglobins and group specific proteins and for red cell acid phosphatases, phosphoglucomutases and glutamic pyruvic transaminases. The findings of Ball et al. (1972) of a positive linear regression of the proportion of male Down's subject heterozygous for haptoglobin on maternal age was confirmed and extended to the female, with both sexes showing changes in respect to paternal age. The increased number of the present sample revealed that this relationship was bimodal with a mode at 35 years for maternal age and 40 years for paternal age. In the other 4 polymorphic systems investigated, no change of heterzygote frequency could be detected.

The phenotype frequencies of serum haptoglobin, serum group specific protein, the second (slower) running zone of the serum leucine naphthylamidase and the serum alkaline phosphatase types of a large sample of subjects with Down's syndrome (254 subjects) are compared with a series of mentally subnormal controls. No phenotype shift could be observed for the haptoglobins, but the frequencies of the serum Gc proteins of the Down's subjects were significantly different to that of the controls. Further investigation of the Gc proteins demonstrated reduced concentrations in the Down's subjects (P=0.05) which together with the failure to establish any change in association between the Gc phenotype contradicts the location of the gene for the Gc proteins being located on the 21st chromosome